Mycobacterium species have shown anti-inflammatory and immuno-regulatory effects in various cases [Zuany-Amorim et al., Nature medicine. 8: 625-629 (2002)]. In people a correlation was found between exposure to BCG or Mtb and inhibition of atopic disorders. Positive tuberculin responses predicted a lower incidence of asthma, lower serum IgE levels, and cytokine profiles biased toward TH1 type. Exposure and response to M. tuberculosis (Mtb) may, by modification of immune profiles, inhibit atopic disorder [Shirakawa et al. (1997)]. Ecological analyses have repeatedly and consistently found an inverse association between the prevalence of tuberculosis in a given country and the prevalence of atopic disorders [von Mutius et al., (2000) ibid, Shirtcliffe et al. (2002) ibid].
The anti-inflammatory and immunoregulatory effects of mycobacteria species have also been observed in several murine models. In allergic asthma mice model induced by ovalbumin (OVA), mice showed high levels of both Th1 and Th2 cytokine transcripts, mice pre-treated with BCG showed transcript levels similar to normal controls, suggesting that the pre-immunization with BCG restores the Th1/Th2 balance [Hubeau et al., (2003)]. The use of killed mycobacterial preparation in the treatment of diseases comprising an immune dysregulation was described in WO03049752. According to this publication, compositions comprising killed mycobacteria or fractions thereof (killed in a manner by which the molecules do not denaturate) are useful for the treatment of Th1-Th2 imbalance, which may result in a variety of conditions including cancer, autoimmune diseases and allergic disorders.
Mycobacterium Cell Wall-associated Lipoglycans
Lipoarabinomannans (LAMs) polysaccharides are major cell surface components of Mycobacterium sp. as Mtb. LAMs are phosphatidylinositol-anchored lipoglycans composed of a mannan core with oligoarabinosyl-containing side-chains with diverse biological activities. These polysaccharide accounts for up to 5 mg g−1 bacterial weight. LAM structures differ according to mycobacterial species, and three general classes of LAM have been described: (i) ManLAM, from the virulent strains Erdman and H37Rv and the avirulent strains H37Ra and BCG [Chatterjee, D., et al. J (1992) ibid; Prinzis, S., et al. Gen Microbiol 139:2649-2658 (1993)], which is characterized by extensive mannose capping of the arabinan termini; (ii) phospho-myo-inositol-capped LAM (PILAM), found in the rapidly growing mycobacteria M smegmatis and M. fortuitum [Nigou, J. Biochimie 85:153-166 (2003)]; and (iii) phosphatidylinositol-capped LAM (AraLAM), which was described in the rapidly growing M. chelonae and lacks mannosylation in its arabinan termini [Guerardel, Y., et al. J Biol Chem 277:30635-30648 (2002)]. Although there is significant heterogeneity between LAM molecules with respect to glycosylation and acylation [Nigou et al. (2003) ibid.], differences in biological activity between the major classes of LAM have been attributed primarily to the heavy mannose capping of ManLAM [Chatterjee et al. (1992). ibid.]
LAMs have been shown to be immunomodulators that modulate cytokine responses and proliferation, in several models. Typically, ManLAM from pathogenic mycobacteria have been reported to be anti-inflammatory, whereas PILAM from nonpathogenic species are pro-inflammatory molecules [Quesniaux et al. (2004). ibid]. TNF and IL-12 release in human dendritic cell line THP-1 and in primary murine macrophages stimulated with LPS was inhibited by ManLAM from M. bovis, BCG and M. tuberculosis [Quesniaux et al. (2004). ibid]. Antigen induced proliferation of Peripheral Blood Mononuclear Cells (PBMC) was inhibited by LAM [Barnes et al. (1992). Ibid].
Inflammation and Immune Responses
Immune processes are probably ongoing and, in most cases, lead to the elimination of antigens without producing clinically detectable inflammation. The development of clinically apparent inflammation indicates that the immune system has encountered either an unusually large amount of antigen, antigen in an unusual location, or antigen that is difficult to digest or that is processed in a way that results in an inflammation or an autoimmune disease. In some diseases, such as rheumatoid arthritis, the initiating agent is unknown or may be normal host tissue components. In others (e.g. systemic lupus erythematosus), inherent or acquired immunoregulatory abnormalities may contribute to the sustained nature of the inflammatory process.
Inflammatory responses and immune induced pathologies mediated by the immune system are divided into four categories, called I, II, III, and IV, which represent four distinct immune mechanisms.
I. Immediate hypersensitivity (allergic, or reaginic acute inflammation).
II. Cytotoxic (inflammation mediated by cytotoxic antibodies).
III. Immune complex (inflammation mediated by immune complex).
IV. Delayed hypersensitivity (chronic inflammation mediated by lymphocytes and macrophages).
Each of the above mechanisms may result in the development of inflammatory conditions which require therapeutic treatment.